Project Summary Muscle wasting syndrome and cachexia are associated with many degenerative diseases, like cancer, AIDS, and other systemic diseases. Muscular atrophy is primarily a result of increased protein degradation in the muscle cells. Muscle satellite cells provide nuclei for post-natal growth and are involved in repair and regeneration of muscle tissue following injury or disease. Activation of satellite cells in response to injury is known to occur to aid in muscle regeneration. In severe states of cancer-related cachexia and age-related wasting, muscle regeneration does not appear to be active. It is unclear why satellite cells in these states are not activated, and it is unclear if these cells possess the ability to replenish during severe atrophy. Unlike conventional mammalian models, several fish species, including the giant danio (Danio aequipinnatus), exhibit an interesting growth type, indeterminate growth, which allows them to recruit new developing muscle fibers from satellite cell populations throughout their lives. This growth physiology phenotype serves as a powerful comparative model system for understanding the activation and proliferation of satellite cells under several conditions. Therefore, it is the long-term goal of the PI to employ the giant danio as a comparative model organism to investigate molecular, hormonal, and physiological characteristics of satellite cells in determinate and indeterminate growth models following trauma or injury. This proposal begins to address this goal by first characterizing the ability, extent, and target molecular aspects of giant danio satellite cells activation following injury. This proposal will investigate specific regulatory pathways uncharacterized in indeterminate growth regulation and injury response (Specific Aim 1) and to identify novel pathways specific to injury response in indeterminate growth using a global approach (Specific Aim 2). The comparative muscle growth culture system is advantageous for prevention, treatment, and design of new therapeutic techniques for muscle trauma and disease states like cachexia and sarcopenia, as it takes advantage of a 'normal'physiological state in an indeterminate model. This approach will be utilized for the identification of early genetic and/or biological markers for muscle disease and even muscle metabolic dysfunction. Thus, the main objectives of the proposed work are to characterize novel pathways in indeterminate muscle growth regulation to identify target pathways of satellite cell activation in indeterminate growth. PUBLIC HEALTH RELEVANCE: Project Narrative Understanding muscle cell growth regulation, regeneration and repair is imperative to developing new preventative and therapeutic strategies for combating muscle wasting syndromes associated with many degenerative diseases. This project is intended to utilize a novel, powerful, comparative muscle growth technique that will allow us to characterize novel pathways regulating muscle cell regeneration by taking advantage of a genetic model exhibiting indeterminate growth. This comparative approach will also give new insight into the regulation of continuous muscle growth seen in non-mammalian models that can be carried over into the mammalian model to test novel prevention and therapy strategies.